ABSTRACT Digital subtraction angiography (DSA) is a proven tool for the diagnosis and treatment of cerebral and peripheral vascular diseases, providing 2D and 3D images of complex vascular anatomy without background anatomic clutter. Still, there are classes of interventional procedures in the thorax and abdomen for which DSA is challenging and often not performed, even though vessels of interest may be obscured by anatomic background. In these body regions, motion of background tissues can be difficult to fully control, leading to subtraction artifacts in DSA images which can easily be as large as the vessel signal itself. The overall goal of this project is to eliminate these limitations through the development of mask-free dual-energy DSA. The clinical application addressed is the interventional treatment of pulmonary embolism, which involves both complex 3D pulmonary artery anatomy and challenging catheter device guidance tasks. In the U.S., pulmonary embolism accounts for as many as 100,000 annual deaths and is a growing cause for hospitalization. Catheter-based treatments using x-ray image guidance are being adopted at most centers for pulmonary embolism patients, yet current imaging techniques remain firmly rooted in 2D non-subtracted methods. Dual-energy DSA (DESA) based on fast kV-switching enables the generation of subtraction images from high and low energy projections which are acquired very close in time, and eliminates the traditional mask phase entirely. We hypothesize that DESA will be insensitive to motion of background tissue when compared to conventional time-subtracted DSA, and additionally, DESA will eliminate background clutter present in non-subtracted angiography. The specific aims are to i) implement a fast kV-switching C-arm prototype and develop dual-energy techniques, ii) evaluate the performance of 2D DESA in phantoms, and iii) evaluate 3D DESA in phantoms and in an animal model of pulmonary embolism. Successful completion will establish a new interventional imaging technique for procedures which traditionally suffer from DSA subtraction artifacts. Beyond the pulmonary application, we anticipate these techniques will be extendable to interventions in the abdomen, the head, and in peripheral procedures.